title: A ligand peptide motif selected from a cancer patient is a receptor-interacting site within human interleukin-11.
abstract: Interleukin-11 (IL-11) is a pleiotropic cytokine approved by the FDA against chemotherapy-induced thrombocytopenia. From a combinatorial selection in a cancer patient, we isolated an IL-11-like peptide mapping to domain I of the IL-11 (sequence CGRRAGGSC). Although this motif has ligand attributes, it is not within the previously characterized interacting sites. Here we design and validate in-tandem binding assays, site-directed mutagenesis and NMR spectroscopy to show (i) the peptide mimics a receptor-binding site within IL-11, (ii) the binding of CGRRAGGSC to the IL-11R alpha is functionally relevant, (iii) Arg4 and Ser8 are the key residues mediating the interaction, and (iv) the IL-11-like motif induces cell proliferation through STAT3 activation. These structural and functional results uncover an as yet unrecognized receptor-binding site in human IL-11. Given that IL-11R alpha has been proposed as a target in human cancer, our results provide clues for the rational design of targeted drugs.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Cardó-Vila
authors.forename: Amado J
authors.initials: AJ
authors.lastname: Zurita
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Giordano
authors.forename: Jessica
authors.initials: J
authors.lastname: Sun
authors.forename: Roberto
authors.initials: R
authors.lastname: Rangel
authors.forename: Liliana
authors.initials: L
authors.lastname: Guzman-Rojas
authors.forename: Cristiane D
authors.initials: CD
authors.lastname: Anobom
authors.forename: Ana P
authors.initials: AP
authors.lastname: Valente
authors.forename: Fábio C L
authors.initials: FC
authors.lastname: Almeida
authors.forename: Johanna
authors.initials: J
authors.lastname: Lahdenranta
authors.forename: Mikhail G
authors.initials: MG
authors.lastname: Kolonin
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D049109:Cell Proliferation; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism*; D053703:Interleukin-11 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D018716:Molecular Mimicry; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000737:chemistry*; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D008024:Ligands; D010446:Peptide Fragments; D050796:STAT3 Transcription Factor